2alpha-lower alkyl dihydro testosterone and derivatives thereof



United States Patent 3 118 915 Zen-LOWER ALKYL nmiznno TESTOSTERONE ANDDERIVATIVES THEREOF Howard J. Ringold and George Rosenkranz, MexicoCity,

Mexico, assignors, by mesne assignments, to Syntex Corporation, acorporation of Panama No Drawing. Filed Jan. 21, 1960, Ser. No. 3,747

Claims priority, application Mexico Feb. 24, 1959 30 Claims. (Cl.260-397.4)

The present invention relates to novel cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly the invention relates to novel androgenic hormoneswhich are Za-IOWGI alkyl and 2a-aralkyl derivatives ofdihydro-testosterone (androstane-l7fi-ol-3- one),l9-nor-dihydrotestosterone, 17u-lower alkyl derivatives and 17-estersthereof.

The novel compounds are active hormones of the andro genic type whichdiffer substantially in their characteristics from the same compoundswithout the substituent at C-2 especially in that they possess superioranabolic action and anti-estogenic activity.

In accordance with the present invention it has been discovered thenovel compounds just described may be prepared by reactingdihydrotestosterone or 17a-lower alkyl-dihydro testosterone with ethylformate and alkali metal hydride to form the correspondingZ-hydroxymethylene derivative, followed by reaction of theZ-hydroxymethylene derivative with an alkyl or aralkyl iodide to formthe corresponding 2-alkyl or aralkyl-2-formyl derivative. Removal ofcarbon monoxide from these last mentioned derivatives produced the novelactive 2-alkyl or aralkyl compounds.

It has also been discovered in accordance with the present inventionthat the novel compounds of this invention may be prepared fromtestosterone or 17ot-alkyl testosterone by forming the2-hydroxymethylene deriva tives and then the Z-alkyl or aralkylderivatives in the same manner as described above. Reduction of the2-alkyl or aralkyl testosterone by hydrogenation in the presence of ahydrogenation catalyst, especially a platinum or palladium catalyst,produces the 2-alkyl or aralkyl dihydro-testosterone or17a-alkyl-dihydrotestosterone.

Reduction of the 3-keto compounds with sodium borohydride gave thecorresponding 3-alcohols.

Similarly, the known 19-nor-testosterone or 19-nor-17alower alkyltestosterones may be treated with ethyl formate and alkali metal hydrideto form the corresponding 2-hydroxymethylene derivatives, which are keyintermediates and active hormones of the type previously set forth.Treatment of the 2 hydroxymethylene l9 nor compounds with a lower alkylor aralkyl iodide gave the corresponding 2-lower alkyl oraralkyl-2'-formyl derivatives which upon removal of carbon monoxide gavethe corresponding active 2-lower alkyl or aralkyl compounds.Hydrogenation of the A -3-keto compounds gave the correspondingsaturated derivatives which could also be reduced to the 3-alcohols.

Conventional esterification gave the active corresponding esters.

The novel active compounds of the present inventiton may therefore becharacterized by the following formulae:

"ice

In the above formulae, R represents a lower alkyl group of less than 7carbon atoms, preferably methyl, ethyl or propyl, or an aralkyl groupsuch as benzyl; R represents hydrogen or lower alkyl; R representshydrogen or an acyl group derived from a hydrocarbon carboxylic acid ofless than 12 carbon atoms or an inorganic acid such as sulfonic acids,sulfuric acid, phosphoric acid and hydrogen halides. The carboxylicacids may be straight or branched chain, saturated or unsaturated,cyclic or mixed cyclic aliphatic, unsubstituted or substituted withhalogen, methoxy or other groups. Typical ester groups are the acetate,propionate, butyrate, hemisuccinate, cyclopentylpropionate, enanthate,phenylpropionate, benzoate, caproate, trimethylacetate, phenoxyacetate,acetoacetate, aminoacetate, and fl-chloropropionate. The esterifiedcompounds may also be in the form of water-soluble salts such as forexample, the alkali metal salts of the hemisuccinates or the disodiumsalt of a phosphate or the hydrohalide salts of esters formed with aminoacids.

The novel compounds of the present invention may be prepared by theprocesses exemplified by the following equations:

OH Ali I I I I lethyl formate OH O H R! a R! H WI ,1 I HO-C'): H O-C= iO 0:

(Ha) H R-i0rlidel l R-i0dide OH OH u RI 1 R! R I R I IQ O 0: I i

(III) (Illa) alumina l l alumina In the above equations, R, R and Rrepresent the same groups as heretofore set forth.

In following the process outlined above, the known 19- nor-testosteroneor 19-nor-l7a-lower alkyl testosterone may be used to prepare thecorresponding 2-alkyl or aralkyl-19-nor-testosterone or 19 nor 17a loweralkyl testosterones.

In practicing the process set forth above, the starting compound whichmay be testosterone, 17a-lower alkyl testosterone such l7wmethyl orl7u-ethyl or the corresponding 4-5 saturated derivative of the alloseries i.e. androstan-l7fi-ol-3-one or 17a-methylorl7a-ethyl-androstan-l7B-ol-3-one, is suspended in an inert organicsolvent such as anhydrous benzene and is then mixed with ethyl formateand sodium hydride. The reaction mixture is then kept for a long periodof time (of the order of one day) at room temperature under a nitrogenatmosphere. The excess of hydride is then decomposed by cautiousaddition of methanol. Cold water is then added to form two layers withthe desired product in the water layer in the form of its sodium salt.The aqueous layer is separated, washed and acidified with dilute mineralacid such as hydrochloric acid and extracted with an organic solventsuch as methylene chloride. From the organic solvent solution thedesired 2-hydroxymethylene intermediate is obtained as by evaporation todryness and recrystallization. The 2-hydroxymethylene compounds aretreated in an organic solvent suspension with sodium hydride and with analkyl or aralkyl iodide (preferably a lower alkyl or benzyl iodide)preferably under reflux conditions and under a nitrogen atmosphere. Thereaction is continued for a long period of time, of the order of 72hours, with successive increments of the iodide being added at intervalsof 24 hours. The mixture is cooled, washed with dilute base to removeunreacted starting material; the product, namely the 2-alkyl oraralkyl-2'- formyl derivative, is recovered from the organic layer byevaporation and recrystallization.

The 2-alkyl or aralkyl-2'-formyl derivatives thus prepared were thentreated with mild base, preferably activated alumina (chromatographictype) of alkaline reaction. This treatment involved passing a benzenesolution of the compounds through a column of the alumina and afterabout a days time, eluting the product from the column with an organicsolvent such as ethyl acetate. The products after crystallization werethe corresponding Zen-alkyl or aralkyl compounds, i.e. Zea-lower alkyl(such as methyl, ethyl or propyl) or benzyl derivatives of testosterone,17a-1OW6I alkyl testosterone or of the saturated compounds such asandrostane-l7fi-ol-3-one or of 1702- loweralkyl-androstan-17,8-ol-3-one. According to the above equation, theZea-alkyl or aralkyl derivatives of testosterone or of the 17a-10W61'alkyl-testosterones are hydrogenated in the presence of a hydrogenationcatalyst, preferably a palladium catalyst and more specificallypalladium on barium sulfate catalyst. After separation of the catalyst,the two isomers formed, i. e.the testane and androstane derivatives wereseparated by chromatog raphy.

In practicing the process outlined above, similarly, the l9-nortestosterone or its 17a-lower alkyl derivatives, suspended in an inertsolvent such as benzene and mixed with ethyl formate and sodium hydride,is maintained under nitrogen atmosphere for a period of time of about 5hours. The salt mixture produced was then treated with acid such asdilute hydrochloric acid and the precipitate thus produced was thecorresponding Z-hydroxymethylene-l9-nor-testosterone or l7a-lower alkylderivative thereof. By then following the procedure as set forth above,the 20t3.1kyi or aralkyl-2-formyl derivatives of l9-nor-testosterone andl9-nor-l7a-lower alkyl-testosterone and the Zia-alkyl or aralkylderivatives of 19-nortestosterone and 19-nor-l7a-lower alkyltestosterone were prepared. To form the corresponding saturatedderivatives of 2a-alky1 and aralkyl-l9-nor-testosterone or19-nor-l7a-lower alkyl testosterones, the A -3-keto compounds aretreated with lithium in liquid ammonia to hydrogenate the double bond.

The novel compounds of this invention are converted to esters byconventional methods of esterification. Este-rification of the A -3-ketocompounds may be effected prior to hydrogenation to form thecorresponding ester of the 4-5 saturated derivatives.

The following specific examples serve to illustrate but are not intendedto limit the present invention:

Example I 2-hydroxymethylene-testosterone was prepared in accordancewith the method of Weisenborn, Remy and Jacobs, J. Am. Chem. Soc., 76,552 (1954).

2.2 g. of 2-hydroxyrnethylene-testosterone and 170 mg. of sodium hydridewere suspended in 50 cc. of benzene and mixed with 10 cc. of methyliodide and the mixture was refluxed under an atmosphere of nitrogen.After 24 hours, additional 10 cc. of methyl iodide was added, followedby 10 more cc. after 48 hours, and the refluxing was continued to atotal of 72 hours. The cooled mixture was washed with 1% sodiumhydroxide solution to remove traces of unreacted starting material andthe organic layer was evaporated to dryness under reduced pressure.Crystallization of the residue from acetonehexane afforded2-methyl-2-formyl-M-androsten-l75-01- 3-one.

1 g. of the above compound was dissolved in benzene and the solution wasused to impregnate a column with g. of alkaline activated alumina. After24 hours the column was eluted with ethyl acetate and the combinedeluates were crystallized from acetone'hexane, thus givinglot-methyl-testosterone melting point -157" C.,

[041 116 (CHCig).

Acetyl'aition with acetic anhydride in pyridine solution by routinemethods yielded the l7-acetate of Zea-methyltestosterone. There was alsoprepared by conventional reaction with acid anhydrides and acid halides,the propionate, cyclopentylpropionate, phenylpropionate and benzoaite.

l g. of 2a-methyltestosterone or its esters dissolved in 100 cc. ofmethanol (ethyl acetate may be used alternatively) was mixed with 100mg. of 5% palladium on barium sulfate catalyst and hydrogenated in anatmosphere of hydrogen at atmospheric pressure and a temperature of 25C. until the equivalent of one mol of hydrogen had been absorbed. Thecatalyst Was filtered, the filtrate was evaporated to dryness and theresidue was chromatographed in a column with activated alumina.

Elution of the column with mixtures of benzene and ether yielded firstZa-methyLtestan-17 8-ol-3-one and then 2amethyl-androstan-l7flol-3-oneor their esters.

The l7-phenylpropionate of Zoc-IIIEthYI-ElldIOStQJI-I7fiol-3-one had amelting point of 132-5" C., [u] +36 (chloroform); thel7-cyclopentylpropionate a melting point of 96l0O C., [a1 +34(chloroform), and the propionate a melting point of 124-126 C. The free20:- methyl-androstan-l7/3-ol-3-one had a melting point of 152454 (3.,[a] +32 (EtOH).

Example 11 Following the method described in Example I, except thatethyl iodide was used instead of methyl iodide, there was obtained2a-ethyltestosterone and 2a-ethyl-dihydrotesterone respectively.

Example Ill Following the method described in Example I, except thatpropyl iodide was used instead of methyl iodide, there was obtained2a-pro-pyltestosterone and 2a-propyldihydrotesterone respectively.

Example IV A mixture of 2.2 g. of Z-hydroxymethylene=testo-sterone, 170mg. of sodium hydride and 50 cc. of benzene was treated with cc. ofbenzyl iodide and the mixture was refluxed for 72 hours under anatmosphere of nitrogen. The cooled mixture was washed with previouslycooled 1% sodium hydroxide solution and evaporated to dryness underreduced pressure. Crystallization from acetonehexane gave2-benzyl-2-formyl-testosterone which upon treatment with alkalineactivated alumina as in Example 1, yielded Z-benzyl-testosterone.

Example V A mixture of g. of dihydrotestosterone, 250 cc. of benzene, 20cc. of ethyl formate and 3 g. of sodium hydride was kept for one day atroom temperature under an atmosphere of nitrogen. The excess of hydridewas decomposed by the cautious addition of methanol and then dilutedwith 200 cc. of water. The aqueous layer was separated, washed withether, acidified and dilute hydrochloric acid and extracted withmethylene chloride. The methylene chloride solution was evaporated todryness and the residue crystallized from acetone-hexane to produceZ-hydroxymethylene-dihydrotestosterone.

The 2 hydroxymethylene dihydrotestosterone was treated with methyliodide in accordance with the method described in Example I, thus giving2-methyl-2'-formyldihydrotestosterone.

The 2-methyl-2-formyl-dihydrotestosterone was treated with alkalineactivated alumina in accordance with the method described in Example I,thus yielding Zen-methylandrostan-l7fi-ol-3-one.

By a similar method using ethyl iodide then was preparedZa-ethyl-androstan l7fl-ol-3-one having a melting point of 169172 C.,[0011) +24 (EtOI-l).

Example VI 2 hydroxymethylene-17a-methyl-testosterone was prepared inaccordance with the method of Weisenborn, Remy and Jacobs, I. Am. Chem.Soc., 76, 552 (1954), starting with 17oc-1'I16'thY1-t68t08t610l16.

2.3 g. of Z-hydroxymethylene l7a-methyl-testosterone and 170 mg. ofsodium hydride suspended in 50- cc. of benzene was treated with 10 cc.of methyl iodide and the mixture was refluxed under an atmosphere ofnitrogen. 10 additional cc. of methyl iodide was added after 24 hours,followed by 10 cc. more after 48 hours, and the refluxing was continuedto a total of 72 hours. The cooled mixture was washed with 1% sodiumhydroxide solution to remove traces of unchanged starting material andthe organic layer was evaporated to dryness under reduced pressure.Crystallization of the residue from acetonehexane afforded2-methyl-2-formyl-l7a-methyl-.A -androsten-l7fi-ol-3-one.

A solution of 1 g. of the above compound in benzene was used toimpregnate a column of g. of alkaline activated alumina. After 24 hoursthe column was eluted with ethyl acetate and the eluates werecrystallized from acetone-hexane to produce 2a,17a-dimethyltestosteronemelting point l50l52 C., [a] +82 (CHC13).

A mixture of '1 g. of 2a,=17a-dimethyl-testosterone, 100 cc. of methanol(ethyl acetate can be used alternatively) and 100 mg. of 5% palladium onbarium sulfate catalyst was hydrogenated under an atmosphere of hydrogenat atmospheric pressure and 25 C. until the equivalent of one mol ofhydrogen had been absorbed. The catalyst was filtered, the filtrate wasevaporated to dryness and the residue was chromatographed in a columnwith activated alumina. Upon elution with mixtures of benzene and ether,there came out first the fractions of 2a,17otdimethyl-testan-17,8-01-3-one and then the fractions of 2a,l7u-dimethylandrostan-175-01- 3 one, melting point 151l54 C., [a] +'8 (CHC-l ExampleVII Following the method described in Example VI, except that ethyliodide was used instead of methyl iodide, there were obtained.2a-ethyl-17a-methyl-testosterone and2aethyl-17a-methyl-dihydrotestosterone (melting point 93- 95 C.)respectively.

Example VIII Following the method described in Example VI, except thatpropyl iodide was used instead of methyl iodide, there were obtained2a-propyl-'17a-methyl-testosterone and2apropyl-l7a-methyl-dihydrotest0sterone respectively.

Example IX A mixture of 2.2 g. of 2-hydroxymethylene-lh-methyltestosterone, mg. of sodium hydride and 50 cc. ofbenzene was treated with 10 cc. of benzyl iodide and refluxed for 72hours under an atmosphere of nitrogen. After cooling, the mixture waswashed with previously cooled 1% sodium hydroxide solution and thenevaporated to dryness under reduced pressure. Crystallization fromacetone-hexane gave 2 benzyl 2' aldehyde-17amethyl-testosterone.

Further treatment of this compound in accordance with the methoddescribed in Example VI, produced Zoebfil'lZYl- 17a-methyl-testosteroneand 2a benzyl-17a-methyl-dihydrotestosterone.

ExampleX Following the method described in Example VI, but starting from2-hydroxymethylene-17a-ethyl-testosterone instead of the I70t-II16llhVlhomologue, there was obtained Za-methyl-l7a-ethyl-testosterone (meltingpoint 141-143 C., [a1 +88) and 2a-methyl17a-ethyl-androstan-l7,8-ol-3-one (melting point 12 8-131 C. [a] +6 Example X I Following themethod described in Example VI, but starting from 2-ihydroxymethylene-17a propyl testosterone instead of the l7u-methylhomologue, there was obtained 2a-methyl-T7a-propyl-testosterone andZea-methyl-17wpropyl-androstan-l7 8-ol-3-one.

In a similar way there can be prepared the following derivatives oftestosterone and of androstan-17f3-ol-3-one: 2a-ethyl-l7u-methyl,2a,l7a-di-et'hyl, 2a-ethyl-l7a-propyl, 2a propyl-17a-methyl, 2a-propyl17oz ethyl, 2a,l7a dipropyl, 2a-benzyl-l7a-methy l, 2a-'benzyl-l7a-ethyland 2a-benzyl-17a-propyl.

Example XII By essentially following the procedure described by A.Behal, A. Ch., 20, 417 (1900), there was prepared the mixed anhydride offormic and acetic acids, by reaction of acetic anhydride with anhydrousformic acid.

Example XIII Following the method described in Example XI, but startingfrom 2a-methyl-l7a-ethyl dihydrotestosterone, there was obtained thel7-formate of 2ot-methyl-17a-ethyldihydrotestosterone.

Example XIV Following the method described in Example XI, except thatthe mixed anhydride of formic and acetic acids was replaced by aceticanhydride, there was obtained the 17-acetate of201,17a-dimethyl-dihydrotestosterone.

Example XV A solution of 1 g. of 2a,17u-dimethyl-dihydrotestosterone in20 cc. of pyridine was treated with 4 g. of cyclopentylpropionicanhydride and heated at 90 C. for 4 days, cooled, poured into ice waterand extracted with methylene chloride; the extract was successivelywashed with dilute hydrochloric acid, 5% aqueous sodium bicarbonatesolution and water, dried over anhydrous sodium sulfate and the solventwas evaporated; chromatography of the residue on neutral aluminafurnished the l7-cyclopentylpropionate of2a,17a-dimethyl-dihydrotestosterone.

Example XVI Following the method of Example XIV, except thatcyclopentylpropionic anhydride is replaced by caproic anhydride therewas obtained the 17-caproate of 2u,17adimethyl-dihydrotestosterone.

Example XVII Following the method of Example XI, 1 g. of 201,174diethyl-dihydrotestosterone was treated with 2 g. of propionic anhydrideto produce the 17-propionate of 201,170;- diethyl-dihydrotestosterone.

Example XVIII A mixture of l g. of 2a,17a-dimethyl-dihydrotestosterone,50 cc. of acetic acid, 10 cc. of acetic anhydride and 1 g. ofp-toluenesulfonic acid monohydrate was kept overnight at roomtemperature, poured into water, heated for half an hour on the steambath, cooled and the precipitate was collected; it was then washed with5% aqueous sodium bicarbonate solution and water, dried andrecrystallized from methylene chloride-methanol, thus yielding the17-acetate of 2oz,17a-dimethyl-dihydrotestosterone.

Example XIX A solution of l g. of 2a,17a-dimethyl-dihydrotestosterone in50 cc. of benzene was treated with 2 g. of caproic anhydride and 500 mg.of p-toluenesulfonic acid monohydrate and kept at room temperature for 3days; after pouring into water the benzene layer was separated, washedwith aqueous sodium bicarbonate solution and water and the solvent wasevaporated. Recrystallization of the residue from acetone-hexaneafforded the caproate of 2a,17u-dimethyl-dihydrotestosterone, identicalwith that obtained in Example XVI.

Example XX A solution of 10 g. of 19-nor-testosterone in 500 cc. ofthiophene free benzene was mixed under nitrogen with 10 cc. of ethylformate, followed by the addition in small portions of 3 g. of sodiumhydride. The mixture was stirred for 5 hours and the resulting mixtureof salts was collected by filtration, washed several times with benzeneand dried. This mixture was added little by little to a stirred dilutehydrochloric acid solution which caused the formation of a precipitate.The stirring was continued for 30 minutes and the precipitate Wascollected, washed with distilled water and dried in vacuo. There wasthus obtained Z-hydroxymethylene-l9-n0rtestosterone which was used forthe next stage without further purification.

The 2-hydroxymethylene-l9-nor-testosterone was added to a suspension of700 mg. of sodium hydride in 200 cc. of benzene, mixed with 40 cc. ofmethyl iodide and the mixture was refluxed under an atmosphere ofnitrogen. After 24 hours an additional 40 cc. of methyl iodide was addedfollowed by another 40 cc. after 24 hours further, and the refluxing wascontinued for still 24 hours more. The cooled mixture was Washed with 1%sodium hydroxide solution and the organic layer was evaporated todryness under reduced pressure. Crystallization of the residue fromacetone-hexane yielded Z-methyl-Z-aldehydo- 19-nor-A-androsten-17/3-ol-3-one.

This 2-methyl-2-aldehydo compound was dissolved in benzene andtransferred to a column with 800 g. of activated alumina. After 24 hoursthe column was eluted with ethyl acetate and the eluates crystallizedfrom acetone-hexane to produce Qu-methyl-l9-nor-testosterone.

By essentially analogous methods, but using ethyl iodide instead ofmethyl iodide, there was prepared 2a-ethyl-l9- nor-testosterone; therewere also obtained, from the corresponding 17u-alkyl derivatives of19-nor-testosterone, 2a,17u-dimethyl-19-nor-testosterone,2a-methyl-l7a-ethyl- 19-nor-testosterone,2a-ethyl-17a-methyl-l9-nor-testosterone and2a,17a-diethyl-l9-nor-testosterone respectively.

Example XXI A solution of 1 g. of 2a-methyl-l9-nor-testosterone,obtained in accordance with the previous example, in a mixture of 10 cc.of dioxane and 10 cc. of absolute ether was added dropwise and undercontinuous stirring to a blue solution of 0.05 g. of lithium metal inliquid ammonia. When the addition of the steroid was complete thesolution had decolorized and then a small amount of lithium was addeduntil the blue color persisted. 1.5 g. of solid ammonium chloride wasadded, the ammonia was allowed to evaporate, the residue was treatedwith Water and chloroform and the organic layer was washed with dilutehydrochloric acid, sodium carbonate solution and water. The solvent wasremoved by distillation and the residue was dissolved in a mixture ofbenzene-hexane and chromatographed in a column of neutral washedalumina. There was thus obtained2a-rnethyl-19-nor-androstan-l7flol-3-one in pure form.

Similarly, the double bond of the other 19-nor-testosterones obtained inaccordance with the previous example was reduced to produce:Za-ethyl-l9-nor-androstan-17flol3-one,2a,17a-dimethyl-19-nor-androstan-17/3-ol-3-one, 2eethyl-17a-methyl-19-nor-androstan-17/3-ol-3-one and 2a,17oc diethyl l9nor-androstan-l7 9-ol-3-one, respectively.

Example XXII A mixture of 1 g. of Za-methyl-19-nor-testosterone, 20 cc.of pyridine and 2 cc. of acetic anhydride was kept at room temperaturefor 16 hours and then poured into ice water. The precipitate wascollected by filtration, and crystallized from acetone-hexane, thusgiving the acetate of Za-methyl-19-nor-testosterone.

Similarly there was also prepared the acetate, propionate,cyclopentylproprionate, benzoate as well as other esters of hydrocarboncarboxylic acids of up to 12 carbon atoms of the character previouslymentioned herein of 2a-methyl-l9-nor-testosterone, of2u-ethyl-l9-nor-testosterone, ofZa-methyl-19-nor-androstan-17fi-ol-3-one, of2e-ethyl-l9-nor-androstan-17B-ol-3-one. Similar esters of the 17-alkylcompounds such as 2e,17a-dimethyl-19-norwherein R is selected from thegroup consisting of lower alkyl and benzyl; R is selected from the groupconsisting of hydrogen and a hydrocarbon carboxylic acyl groupcontaining up to 12 carbon atoms; R is selected from the groupconsisting of hydrogen and lower alkyl.

2. Zen-IOWGI alkyl-17a-lower alkyl-androstan-1718-ol-3- one.

. 2ot-benzyl-l7a-lower alkyl-androstan-17fl-o1-3-0ne. 2a,17u-dimethy1-androstan-17fl-ol-3-one.

. 2a-ethyl-17u-methyl-androstan-17,8-ol-3-one.

. Zea-lower alkyl-androstan-17B-ol-3-one.

Za-methyI-androstan-l7B-ol-3-one.

. 2a-propyl-androstan-17 8-ol-3-one.

. 2u-benzyl-androstan-1713-ol-3-one.

10. The hydrocarbon carboxylic acid esters containing up to 12 carbonatoms of 2a-lower alkyl-17a-lower alkylandrostan-17/3-ol-3-one.

11. The acetate of 2a,17u-dimethyl-androstan-17 8-01- 3-one.

12. The propionate of 2a,17ot-diethyl-androstan-17,8- ol-3-one.

14. The hydrocarbon carboxylic acid esters containing up to 12 carbonatoms of 2a-lower alkyl-androstan- 17/3-ol-3-0ne.

15. The propionate of Za-methyl-androstan-l75-01-3- one.

16. The phenylproprionate of Za-methyl-androstanl7fi-ol-3-one.

17. The acetate of 2u-methyl-androstan-17fi-ol-3-one.

18. The benzoate of 2u-rnethyl-androstan-17,8-ol-3-one.

19. A compound having the following formula:

wherein R is selected from the group consisting of lower alkyl andbenzyl; R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R isselected from the group consisting of hydrogen and lower alkyl.

20. Zea-lower alkyl-l9-nor-androstan-17B-ol-3-one.

21. Zen-methyl-19-nor-androstan-17fl-ol-3-one.

22. Zia-ethyl-19-nor-androstan-17fi-ol-3one.

23. The hydrocarbon carboxylic acid esters containing up to 12 carbonatoms of Zea-lower alkyl-19-nor-androstan-17fl-ol-3-one.

24. The acetate of 2a-methyl-l9-nor-androstand7fi-ol- 3-one.

25. The propionate of 2a-rnethyl-19-nor-androstan- 17/3-oi-3-one.

26. 20,17ot di-lower alkyl-19-nor-androstan-17 8-013- one.

27. 2a,17a-dimethyl-19-nor-androstan-17fi-ol-3-one.

28. 2oz ethyl Wot-methyl-19'-nor-andro-stan-175-01-3- one.

29. A compound of the formula 0 R GIL;

HaC

wherein R is selected from the group consisting of H and Ac; wherein Acis the acyl radical of a hydrocarbon carboxylic acid containing from 2to 3 carbon atoms.

30. A compound selected from the group consisting of those of thefollowing formulas:

and

References Cited in the file of this patent UNITED STATES PATENTSDjerassi et al. July 24, 1956 Colton Sept. 1, 1959

30. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THEFOLLOWING FORMULAS: